C19ORF80 Human

What is C19ORF80 and what alternative names are used in the literature?

C19ORF80 (Chromosome 19 Open Reading Frame 80) is a gene located on chromosome 19p13.2 in humans. It has been independently studied by multiple research groups, resulting in several alternative names:

• Lipasin: Highlighting its role in lipid metabolism

• Betatrophin: Reflecting its proposed role in β-cell proliferation

• Angptl8: Indicating its relationship to the angiopoietin-like protein family

• RIFL: Refeeding Induced Fat and Liver expressed protein

The official designation according to the HUGO Gene Nomenclature Committee is C19orf80 for humans and Gm6484 for mice. These various names reflect ongoing debate about the primary physiological function of this protein .

What is the basic structure and cellular localization of C19ORF80?

The C19ORF80 transcript consists of 4 exons encoding a 198-amino acid polypeptide. Sequence analysis reveals it's a transmembrane protein with a signal peptide and potential myristoylation site at the N-terminal region .

Regarding cellular localization, immunofluorescence analysis shows C19ORF80 exhibits a vesicle-like distribution pattern in the cytoplasm. Specifically, it has been observed:

• Adjacent to lipid droplet surfaces

• Associated with lysosomal-associated membrane protein 2 (LAMP2)

• Partially co-localized with calnexin (CANX), indicating some presence in the endoplasmic reticulum

• Rarely detected in mitochondria

Subcellular fractionation confirms C19ORF80 co-fractionates with LAMP2 and CANX, supporting its presence within lysosome/endosome and ER-associated compartments .

What methods are available for detecting C19ORF80 in experimental samples?

Researchers have several options for detecting C19ORF80:

• ELISA:

  • Sandwich ELISA kits are commercially available for quantitative measurement

  • Typical detection ranges: 0.156-10 ng/mL

  • Minimum detection limits: around 0.056-0.156 ng/mL

  • Applicable to various sample types including cell culture supernatant, cell lysate, plasma, serum, and tissue homogenate

• Western Blotting:

  • Effective for detecting C19ORF80 protein expression in cell and tissue lysates

  • Allows semi-quantitative analysis of expression levels

• Quantitative RT-PCR:

  • Used to measure C19ORF80 mRNA expression

  • Can determine transcriptional responses to stimuli like thyroid hormone (T3)

• Immunofluorescence microscopy:

  • Visualizes subcellular localization

  • Reveals the vesicle-like distribution pattern

  • Can be combined with organelle markers to determine precise localization

How can C19ORF80 expression be experimentally modulated?

Several approaches have been validated for modulating C19ORF80 expression:

• Thyroid hormone (T3) treatment:

  • T3 upregulates both mRNA and protein levels of C19ORF80 in a dose- and time-dependent manner

  • This effect is mediated through thyroid hormone receptors (THRs), including both THRA and THRB

• Genetic overexpression:

  • Transfection with expression vectors containing C19ORF80 cDNA

  • Useful for studying effects of increased C19ORF80 on autophagy and lipid metabolism

• RNA interference:

  • siRNA or shRNA targeting C19ORF80

  • Knockdown of C19ORF80 has been shown to obstruct T3-activated autophagy and lipolysis

• Additional regulators:

  • Gene expression profiling studies indicate C19ORF80 is regulated by various stimuli, including HCV-1b, interferon-α, cationic amphiphilic drugs, caloric intake, and trichostatin A

What is the relationship between thyroid hormone and C19ORF80 expression?

Thyroid hormone (T3) is a significant regulator of C19ORF80 expression through the following mechanisms:

• Transcriptional activation:

  • T3 transactivates C19ORF80 gene expression through binding to nuclear thyroid hormone receptors (THRs)

  • Both THRA and THRB receptor subtypes can mediate this response

  • qRT-PCR confirms specific upregulation of C19ORF80 mRNA by T3

• Dose and time dependence:

  • T3 stimulates C19ORF80 in a dose-dependent manner

  • The response also shows clear time-dependent characteristics

• Protein expression:

  • Corresponding increases in C19ORF80 protein levels follow T3 stimulation

  • This response is observed in cells expressing either THRA or THRB

  • No significant C19ORF80 protein is detected in control cells (HepG2-Neo)

While T3 clearly regulates C19ORF80, the precise molecular mechanisms, including specific response elements in the promoter region, remain to be fully established .

How does C19ORF80 influence autophagy pathways?

C19ORF80 plays a critical role in activating autophagy as evidenced by multiple experimental findings:

• Direct effects on autophagy markers:

  • Ectopic expression of C19ORF80 results in accumulation of acidic vacuoles in cells

  • C19ORF80 overexpression induces increased LC3-II levels (a marker of autophagosome formation)

  • It leads to decreased SQSTM1/p62 levels, indicating enhanced autophagic degradation

• Autolysosome maturation:

  • C19ORF80 activates the complete autophagy process through to autolysosome maturation

  • Treatment with autolysosome maturation inhibitors (ammonium chloride and chloroquine) suppresses C19ORF80-activated autophagy

• T3-C19ORF80-autophagy axis:

  • Knockdown of C19ORF80 obstructs T3-mediated activation of autophagy

  • This indicates T3 induces autophagy specifically through C19ORF80

• Visualization evidence:

  • In cells transfected with mRFP-GFP-LC3 reporter, C19ORF80 overexpression increases RFP-LC3 punctate structures

These findings demonstrate that C19ORF80 is both necessary and sufficient for activating autophagy in liver cells, providing a mechanistic link between T3 signaling, C19ORF80 expression, and autophagic activity .

What mechanisms underlie C19ORF80's role in lipid metabolism?

C19ORF80 influences lipid metabolism through several mechanisms:

• Lipid droplet turnover:

  • C19ORF80 participates in the turnover of lipid droplets through autophagy

  • Immunofluorescence shows C19ORF80 exhibits a vesicle-like pattern adjacent to lipid droplet surfaces

• T3-mediated lipid metabolism:

  • T3 enhances lipid metabolism, as measured by increased oxygen consumption rates

  • This effect appears to be mediated through C19ORF80-activated processes

• Autophagy-dependent lipid metabolism:

  • T3 regulates lipid metabolism through a C19ORF80-activated autophagic process

  • Treatment with autolysosome maturation inhibitors suppresses both T3-activated autophagy and lipid metabolism

  • This suggests C19ORF80's effects on lipid metabolism are dependent on autophagy

• Experimental evidence:

  • Overexpression of C19ORF80 activates lipid metabolism

  • Knockdown of C19ORF80 blocks T3-activated lipolysis

These findings highlight C19ORF80's role in regulating lipid metabolism, potentially through modulating autophagic degradation of lipid droplets, a process sometimes termed "lipophagy."

How do genetic variations in C19ORF80 affect lipid parameters?

Two significant polymorphisms in C19ORF80 have been associated with altered lipid profiles:

These contrasting effects (R59W associated with lower HDL-C, while Q121* is associated with higher HDL-C) highlight the complex relationship between C19ORF80 and lipid homeostasis .

What controversies exist regarding C19ORF80's role in β-cell proliferation?

The role of C19ORF80/betatrophin in β-cell proliferation remains highly controversial:

This controversy represents a critical area for further research, particularly clarifying the specific conditions under which C19ORF80/betatrophin might influence β-cell proliferation and determining whether its effects are direct or indirect.

What is the relationship between C19ORF80 and other Angptl family members?

The relationship between C19ORF80/Angptl8 and other Angptl family members remains incompletely understood:

• Family relationship:

  • C19ORF80 is also known as Angptl8, suggesting structural or functional relationships to the angiopoietin-like protein family

  • Angptl3 and Angptl4 are mentioned as related proteins

• Research gaps:

  • The search results explicitly state that "the relationship among lipasin, Angptl3 and Angptl4, remain elusive"

  • This indicates that precise molecular interactions and functional relationships between these proteins require further investigation

This represents a significant area for future research, particularly regarding:

• Structural similarities and differences among Angptl family members

• Potential functional redundancy or complementarity

• Shared or distinct regulatory mechanisms

• Coordination of activities in lipid metabolism

What methodological approaches can resolve current contradictions in C19ORF80 research?

To address controversies in C19ORF80 research, several methodological approaches would be valuable:

• Standardized experimental conditions:

  • Using consistent cell lines and animal models across studies

  • Standardizing measurement techniques for detecting C19ORF80

  • Defining consistent parameters for assessing biological effects

• Multi-omics approaches:

  • Combining proteomic, transcriptomic, and metabolomic analyses

  • Identifying interaction networks through unbiased approaches

  • Correlating genetic variations with functional outcomes

• Advanced imaging techniques:

  • Further characterizing subcellular localization using super-resolution microscopy

  • Live-cell imaging to track C19ORF80 trafficking and dynamics

  • Correlative light-electron microscopy to understand structural relationships

• Genetic models:

  • Generating conditional knockout models to study tissue-specific effects

  • CRISPR-engineered cell lines with specific C19ORF80 variants

  • Humanized mouse models expressing human C19ORF80 variants

• Reproducibility initiatives:

  • Direct replication studies of key findings, particularly regarding β-cell proliferation

  • Multi-laboratory collaborative projects with standardized protocols

  • Pre-registered experimental designs to reduce publication bias